Tardive dyskinesia (TD) is a side effect of chronic antipsychotic medication characterized by involuntary movements of the tongue, the orofacial region, trunk, and extremities. Its reported prevalence varies from 16% to 43%, with an annual incidence rate of around 5% (reviewed in Tarsy and Baldessarini, 2006). Patients with this condition often struggle with the immediate difficulties of motor function, but also with adhering to treatment, discrimination, and poorer quality of life, so predicting which patients are vulnerable to TD remains a high priority for psychiatrists in treatment selection. TD has a significant genetic component (Müller et al, 2001). Although such abnormal movements have been described before neuroleptics were given to patients, the etiology of TD remains unknown. A number of mechanisms have been hypothesized, including GABA insufficiency, free radical-mediated neuronal injury, and structural abnormalities in brain regions involved in motor function such as the caudate nucleus. A traditional hypothesis postulates TD as being caused by hypersensitivity of dopamine receptors induced by dopamine receptor antagonizing medications such as antipsychotics. In such a case, it is hypothesized that prolonged antagonism (or blocking) of dopamine receptors may induce a potentially irreversible increased affinity to dopamine. This results in an imbalance between inhibiting and activating mechanisms of the motor system a shift towards the activating mechanism and hence induce abnormal movements.
Molecular genetic studies investigating the role of the dopaminergic system in TD have been recently reviewed (Müller et al, 2004). Genes involved in the transportation (DAT1) or metabolism (MAOA, COMT, MAOB) of dopamine, have mainly produced negative findings in TD. D3 has received much attention in TD studies in light of several positive association results where the Ser9Gly polymorphism was found to be associated with TD (Lerer et al, 2002).
Anatomically, the dopamine receptor DRD3-coded D3 receptor is localized to the ventral striatum and putamen of the basal ganglia, an area of the brain that is involved in locomotor control (Suzuki et al, 1998). D3 receptor levels have been shown to increase in response to chronic haloperidol administration in rat brains (Buckland et al, 1992). The increase was also observed in human postmortem schizophrenia patient basal ganglia after neuroleptic treatment (D'Souza et al, 1997). R-(+)-7-OH-DPAT, a D3-selective agonist, inhibited locomotor activity when injected into the nucleus accumbens of rats (Kling-Petersen et al, 1995), while D3 antagonists increased motor activity (Gyertyan and Saghy, 2004). The findings were corroborated in mice lacking functional D3; they were hyperactive (Accili et al, 1996).
The Ser9Gly polymorphism was studied previously because of its role in D3 affinity for dopamine as revealed in CHO cells (Lundstrom and Turpin, 1996). Although these findings could not be replicated in other studies, the Gly allele (or Gly/Gly genotype) has been found associated with TD in a combined analysis involving 780 patients and in a subsequent meta-analysis including seven studies (Lerer et al, 2002) although the odds ratio for predicting risk is low at around 1.3. The mixed results among the different studies could be due to sample sizes, ethnic background differences or possibly by the lack of a comprehensive analysis of the DRD3 gene. Variations in the DRD3 gene, in addition to Ser9Gly, may contribute to TD risk or severity.
There is a need in the art for new genetic markers that are associated with tardive dyskinesia. Further, there is a need in the art for methods to determine if a subject is likely to develop tardive dyskinesia in response to antipsychotic drug therapy. Further, there is a need in the art for new screening methods to permit drugs or other pharmaceutical products to be tested on subjects susceptible to tardive dyskinesia from antipsychotic therapy.